This Program Project Grant requests funds for the continuation of a multidisciplinary programmatic study of the anxiety disorders. The overall thrust is to both validate and refine the nosology of anxiety disorders using familial, developmental, epidemiologic, pharmacological challenge and molecular biologic criteria. The objective of the family study, under the direction of Dr. Abby Fyer, is to use patterns of longitudinal course of familial transmission to validate the distinctions between the anxiety disorders. We now also use the longitudinal sequences of anxiety disorder comorbidity as well as symptomatic heterogeneity within the anxiety disorders as dissecting tools. The child study, under the direction of Dr. Rachel Klein, will include prospective longitudinal studies, and the development of control groups of children of parents with pure as well as comorbid disorders and non-ill parents. This high risk study will cross validate the retrospective findings of the family study. The Hispanic study, under the direction of Dr. Michael Liebowitz will focus on the ataque syndrome as a marker of a culturally sanctioned label for anxiety and/or affective dysregulation in the Hispanic population. An informed systematic nosological appraisal will be uniquely validated for panic disorder by biological challenges. The epidemiologic component, under Dr. Myrna Weissman, will continue to analyze the already collected ECA data in consultation with clinicians from the Program. Analytic methods developed for panic disorder will be applied to other anxiety disorders. Further, crossnational comparisons should cast light on the variation of syndromes and risk factors. The linkage study, supervised by Dr. AbbyFyer in collaboration with Dr. Conrad Gilliam, will use highly polymorphic DNA markers spanning the entire human genome to test for linkage to disease phenotypes in a collection of extended pedigrees, augmented by genetic association studies.